Is GLIS2 p.Ala437= (c.1311A>C) pathogenic?

GLIS2 p.Ala437= (c.1311A>C) is classified Benign in GLIS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Common (popmax 59.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with nephronophthisis.

What condition is associated with GLIS2 p.Ala437= (c.1311A>C)?

GLIS2 p.Ala437= (c.1311A>C) is associated with nephronophthisis, nephronophthisis 7 (ClinVar).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GLIS2 p.Ala437=

Q: How common is GLIS2 p.Ala437= (c.1311A>C) in the general population?

GLIS2 p.Ala437= (c.1311A>C) is common (popmax 59.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1311A>C · rs3810817 · VCV96223

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 59.9%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.13	GERP -1.6, phastCons 0.54
Overall
CADD	2.044	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 59.9% African / African-American · 43,773/73,116 alleles

Filtering AF 59.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.2%

Overall 14.9% 230,118/1,548,916 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	59.9%	2
Admixed American	23.4%	4
Middle Eastern	18.1%	6
Remaining individualsnot grpmax-eligible	16.8%	6
Ashkenazi Jewishnot grpmax-eligible	15.4%	6
South Asian	14.9%	7
Finnishnot grpmax-eligible	13.6%	7
European (non-Finnish)	11.7%	9
East Asian	10.5%	10
Amishnot grpmax-eligible	9.32%	11

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GLIS2
Protein: p.Ala437=
Coding: c.1311A>C
MANE Select: NM_032575
dbSNP: rs3810817
Type: single nucleotide variant
Location: chr16:4337260 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 55.47

Full GLIS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 7

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

GLIS2 p.Ala437Thr Uncertain significance ★★ ⚠ same residue
GLIS2 p.Ala437Pro Uncertain significance ★ ⚠ same residue
GLIS2 c.*1826C>T Uncertain significance ★★ same condition
GLIS2 c.*916G>A Uncertain significance ★★ same condition
GLIS2 p.Ala19Val Uncertain significance ★★ ⚠ same condition
GLIS2 p.Ala210Thr Uncertain significance ★★ same condition
GLIS2 p.Ala360Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg102Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/glis2-p-ala437 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown